Method and apparatus using IDSTM for multi-agent therapy

ABSTRACT

A method and apparatus using IDS™ technology to calculate new agent doses in a multi-agent therapy. The overall proportion of each agent is determined by the amount of agent as it relates to the dosing range. The overall proportion as well as the intrinsic potency of the agent is used to determine the total proportional effect which each agent has on the surrogate marker. This parameter is then inserted into the four-parameter equation for calculating dose by adjusting the proportional change in marker that is attributed to the activity of the agent.

FIELD OF THE INVENTION

[0001] The present invention relates generally to a method and apparatususing IDS™ (Intelligent Dosing System™) technology for multi-agenttherapy. More particularly, the present invention relates to a methodand apparatus for use in treating a patient with multiple agents tooptimize therapy and to prevent an adverse response. The presentinvention can utilize either biological substance levels or othersurrogate markers to determine the effectiveness of the dosing regimenand, if necessary, to suggest a new more optimal regimen.

[0002] A The term “agent” as used herein includes, but is not limitedto: vaccines; serums; drugs; adjuvants to enhance or modulate aresulting immune response; vitamin antagonists; medications; autologouswhole-cell vaccines (using cells derived from a patient's own tumor);allogenic whole-cell vaccines (using cancer cell lines established invitro and then used to vaccinate multiple patients); tumor specificantigen/tumor associated antigen (TSA/TAA) based vaccines and hormonalautoimmunization approaches; all other cancer vaccines; Melacine;CancerVax; immune-boosting interferon; peptides; dendritic cells havingmelanoma protein thereon; interleukin-12; substances which stimulate orenergize blood cells known as CD8 T cells; genes which makeinterleukin-12; tumor cells weakened by genes which make interleukin-12;substances which block blood-vessel formation to prevent growth oftumors; immunized cells; recombinant subunit vaccines; DNA vaccines;live recombinant viral vector vaccines; live recombinant bacterialvector vaccines; live-attenuated vaccines; whole-inactivated vaccines;virus-like particle vaccines; synthetic peptide vaccines; “Jennerian”vaccines; complex vaccines; and combinations of two or more of theforegoing.

[0003] The term “surrogate marker” as used herein means all surrogatemarkers and includes, but is not limited to: a measurement of biologicalactivity within the body which indirectly indicates the effect oftreatment on a disease state or on any condition being treated; and anymeasurement taken on a patient which relates to the patient's responseto an intervention, such as the intervention of a biological substanceintroduced into or on the patient. For example, CD4 cell counts andviral load are examples of surrogate markers in HIV infection.

BACKGROUND OF THE INVENTION

[0004] When a patient begins taking an agent or any medication for alength of time, a titration of the amount of agent taken by the patientis necessary in order to achieve the optimal benefit of the agent, andat the same time to prevent any undesirable side effects that taking toomuch of the agent could produce. Thus, there is a continuous balancebetween taking enough of the agent in order to gain the benefits fromthat agent, and at the same time not taking so much agent as to illicita toxic event.

[0005] There is large inter-individual variability in the patientbiological interactions and/or the patient pharmocodynamic andpharmacokinetic interactions of agents. What may be an appropriate agentdose for one individual, may be too much or too little for another. Aphysician was required to estimate the correct agent dosage for apatient and then to experiment with that dosage, usually by trial anderror, until the correct dosage was achieved. Likewise, the FDA labelingof a agent suggests dosages based on epidemiological studies and againdoes not account for inter-individual variability. Non-linear leastsquares modeling methods involve the use of large amounts of datarelating to a general population in order to calculate a best fit. Muchlike linear regression models, this method cannot take into account thevariability between people with the same population characteristics.

[0006] Bayesian analysis is another method used to relate agent dose toefficacy. This method employs large-scale population parameters tostratify a population in order to better characterize the individuals.This method does not take into account the changes that can occur withina person over time, and as a result cannot reliably estimate dosages.

[0007] Pharmacokinetic compartment modeling has had success with someagents, but because the models are static and cannot adapt themselves tochanges within a population or a patient, they are once againundesirable for dynamically determining agent dosages.

[0008] Expert systems have been developed using similar technology topredict specific drug dosages for specific immunosuppressant drugs (see,e.g., U.S. Pat. Nos. 5,365,948, 5,542,436 and 5,694,950). Thesealgorithms, however, are not generic and only use immunosuppressantblood levels. Each algorithm is specific to an individual specificimmunosuppressant drug. As it stands, these inventions cannot be appliedto other agents and do not have a non-linear feedback loop mechanism.

[0009] Applicant's U.S. Pat. No. 6,267,116 discloses a majorbreakthrough in IDS™ technology, but can only accommodate one drug at atime.

[0010] It is a desideratum of the present invention to avoid theanimadversions of conventional systems and techniques

SUMMARY OF THE INVENTION

[0011] The present invention provides in one embodiment thereof a methodof calculating the next best dose for each agent of a multi-agenttherapy which a patient may be using, comprising the steps of: acceptingas first inputs the patient's current doses of a plurality of agentswhich the patient may be using; accepting as second inputs one or morenumerical markers indicating one or more responses of the patient; andcalculating new agent doses for said plurality of agents as a functionof said first inputs, said second inputs, and contributions which eachagent makes to an overall effect to be achieved by said multi-agenttherapy.

[0012] The present invention provides in a further embodiment thereof astorage device having stored thereon an ordered set of instructionswhich, when executed by a computer, performs a predetermined method,comprising: first means for accepting as first inputs a patient'scurrent doses of a plurality of agents which the patient may be using;second means for accepting as second inputs one or more numericalmarkers indicating one or more responses of the patient; and third meansfor calculating new agent doses for said plurality of agents as afunction of said first inputs, said second inputs, and contributionswhich each agent makes to an overall effect to be achieved by saidmulti-agent therapy.

[0013] The present invention provides in another embodiment thereof anapparatus for calculating the next best dose for each agent of amulti-agent therapy which a patient may be using, comprising: firstmeans for accepting as first inputs the patient's current doses of aplurality of agents which the patient may be using; second means foraccepting as second inputs one or more numerical markers indicating oneor more responses of the patient; and third means for calculating newagent doses for said plurality of agents as a function of said firstinputs, said second inputs, and contributions which each agent makes toan overall effect to be achieved by said multi-agent therapy.

DESCRIPTION OF THE DRAWINGS

[0014]FIG. 1 shows a flow chart of the process by which new doses of anagent, of a multi-agent therapy, are determined according to a portionof the method of the invention.

[0015]FIG. 2 shows an apparatus for use in calculating new doses of aplurality of agents used in a multi-agent therapy according to theinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0016]FIG. 1 shows a flow chart of a portion of the overall process oftreating a patient using this expert system. The actual expert systemperforms many steps which are described herein, whereas only the stepsshown in blocks 10 and 12 are generally indicated the flow chart.

[0017] This expert system includes a general purpose computer, shown inFIG. 2, comprising an input means, preferably a keyboard 20 and/or amouse 22, an output means 30, preferably a video display screen, a datastorage means 50, preferably a hard disk drive, and a processor. Theexpert computer program receives input data from a physician regardingthe patient's current agent dose, the maximal dose range for thatparticular agent, and the percent response of the patient based on thesurrogate markers used to monitor that agent.

[0018] Also characterized is the patient's response to the last dosingcycle as well as a dose response constant. This allows the expert systemto individualize the patient dosing based on the patient's individualresponse to that particular agent. The system calculates a reviseddosage based on the data input by the physician.

[0019] The software portion of the invention includes a user interfaceportion 100 to receive the input data and to output the revised dosageinformation, and a data analysis portion 110, which calculates the newdosage information based on the input data.

[0020] A physician prescribes a agent for a patient based on the FDArecommended dose on the label of the agent. The physician thenre-evaluates the patient, usually daily, either in person or remotelydepending on the agent being prescribed.

[0021] During the subsequent evaluations by the physician, the surrogatemarkers are monitored and sequentially compared to determine if thereare any toxicities associated with the agent. Also the numerical markerswill be evaluated to see if the desired effect of the agent is beingachieved.

[0022] Given the effectiveness of the agent's action relative to thesurrogate markers, a change in agent dose is calculated by the system.Conversely, by employing this system, one could determine the expectedresult of the agent dose change on the surrogate marker.

[0023] The present invention will now be described in detail withrespect to 2-agent IDS™ therapy and 3-agent IDS™ therapy, although it isapplicable to any number of agents.

Using the IDS™ with Multi-Agent (2 Agents) Therapy

[0024] When using a multi-agent regimen to treat patients it isnecessary to calculate the next best dose for each agent the patient isusing. The IDS™ technology in the form disclosed in applicant's U.S.Pat. No. 6,267,116 can only dose one agent at a time. The followingcalculations show how to use the concept of the IDS™ and the doseresponse methodology to perform multiple computations, each based on theproportional response which a particular agent has on the overallresponse that is to be achieved.

[0025] The concept underlying this multi-agent dosing model is that eachagent has some contribution to the overall effect. This contribution isdetermined by the amount of each agent the patient is using as well asthe intrinsic potency of each agent. The overall proportion of eachagent is determined by the amount of agent as it relates to the dosingrange. The overall proportion as well as the intrinsic potency of theagent is used to determine the total proportional effect which eachagent has on the surrogate marker. This parameter (FOE1 or FOE2) is theninserted into the four-parameter equation (NAD) for calculating dose byadjusting the proportional change in marker that is attributed to theactivity of the agent.

[0026] To Calculate the First Agent

NAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1}+LV1

[0027] To Calculate the Second Agent

NAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2

[0028] where:

EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1

EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1

[0029] if CANM1<DANM1 and EANM2>CANM1,

[0030] or

[0031] if CANM1>DANM1 and EANM2<CANM1,

[0032] then

LV1−RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)]

[0033] if CANM1<DANM1 and EANM2<CANM1,

[0034] or

[0035] if CANM1>DANM1 and EANM2>CANM1,

[0036] then

LV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)]

[0037] if CANM2<DANM2 and EANM2>CANM2,

[0038] or

[0039] if CANM2 >DANM2 and EANM2 <CANM2,

[0040] then

LV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)]

[0041] if CANM2<DANM2 and EANM2<CANM2,

[0042] or

[0043] if CANM2>DANM2 and EANM2>CANM2,

[0044] then

LV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)]

[0045] PAD1=Previous agent dose of the first agent

[0046] PAD2=Previous agent dose of the second agent

[0047] CAD1=Current agent dose of the first agent

[0048] CAD2=Current agent dose of the second agent

[0049] NAD1=New agent dose of the first agent

[0050] NAD2=New agent dose of the second agent

[0051] PADM1=Previous agent numerical marker for the first agent

[0052] CANM1=Current agent numerical marker for the first agent

[0053] CANM2=Current agent numerical marker for the second agent

[0054] DANM1=Desired agent numerical marker for the first agent

[0055] DANM2=Desired agent numerical marker for the second agent

[0056] FOE1=Factor of effect the first agent has on its associatednumerical marker

[0057] FOE2=Factor of effect the second agent has on its associatednumerical marker

[0058] HIGH1=The input parameter that is the high dose range for thefirst agent

[0059] HIGH2=The input parameter that is the high dose range for thesecond agent

[0060] RESPONSE1=Percent of total dose available for individualizingpatient dose of the first agent

[0061] RESPONSE2=Percent of total dose available for individualizingpatient dose of the second agent

[0062] 1.3^ (CAD1/HIGH1)=1.3 raised to an exponent of (CAD1/HIGH1)

[0063] 1.3^ (CAD2/HIGH2)=1.3 raised to an exponent of (CAD2/HIGH2)

[0064] To Calculate the Proportion of Effect Based on the Amount ofAgent and the Agent's Intrinsic Effect

[0065] Agent1 Effect=1

[0066] Agent2 Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)} \times {Agent2}\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}}}$${FOE2} = \frac{{Total}\quad {Proportional}\quad {Effect2}}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}}}$

EXAMPLE

[0067] Gemzar Dose is 5000

[0068] Taxol Dose is 250

[0069] Assume both agents have an equal effect.

[0070] Current Marker (ANC) is 0.5

[0071] Desired Marker (ANC) is 1.8${{Taxol}\quad {Proportion}} = {\frac{250/50}{\left( {{250/500} + {5000/3300}} \right)} = {\frac{0.5}{2.0152} = 0.2481}}$${{Gemzar}\quad {Proportion}} = {\frac{5000/3300}{\left( {{250/500} + {5000/3300}} \right)} = {\frac{1.5152}{2.0152} = 0.7519}}$${{Total}\quad {Proportional}\quad {Taxol}\quad {Effect}} = {{\frac{250/50}{\left( {{250/500} + {5000/3300}} \right)} \times 1} = 0.2481}$${{Total}\quad {Proportional}\quad {Gemzar}\quad {Effect}} = {{\frac{5000/3300}{\left( {{250/500} + {5000/3300}} \right)} \times 1} = 0.7519}$

 FOE1=0.2481/(0.2481+0.7519)=0.2481

FOE2=0.7519/(0.2481+0.7519)=0.7519

[0072] Calculate  Taxol  Dose${{New}\quad {Taxol}\quad {{Dose}{\quad \quad}({NAD1})}} = {250 - \left\{ {\left\lbrack \frac{\frac{\left( {1.8 - 0.5} \right) \times 0.2481}{0.5}}{1 + \left( {250/500} \right)} \right\rbrack \times 250} \right\}}$${{New}\quad {Taxol}\quad {{Dose}{\quad \quad}({NAD1})}} = {250 - \left\{ {\left\lbrack \frac{\frac{0.3225}{0.5}}{1.5} \right\rbrack \times 250} \right\}}$

 New Taxol Dose (NAD1)=250−{0.4300×250}

New Taxol Dose (NAD1)=250−107.5

New Taxol Dose (NAD1)=142.5

[0073] Calculate Gemzar Dose${{New}\quad {Gemzar}\quad {{Dose}{\quad \quad}({NAD2})}} = {5000 - \left\{ {\left\lbrack \frac{\frac{\left( {1.8 - 0.5} \right) \times 0.7519}{0.5}}{1 + \left( {5000/3300} \right)} \right\rbrack \times 5000} \right\}}$${{New}\quad {Gemzar}\quad {{Dose}{\quad \quad}({NAD2})}} = {5000 - \left\{ {\left\lbrack \frac{1.1884}{2.5152} \right\rbrack \times 5000} \right\}}$

 New Gemzar Dose (NAD2)=5000−{0.7725×5000}

New Gemzar Dose (NAD2)=5000−3862.5

New Gemzar Dose (NAD2)=1137.5

[0074] Loop Math

EANM1={[−1×(250−350)/350]×[1+(350/500)]×0.4}+0.4

[0075] Note: x by−1 because PAD1>CAD1

EANM1={[0.2857×1.7]×0.4}+0.4

EANM1={0.4857×0.4}+0.4

EANM1=0.5943

EANM2={[−1×(5000−6000)/6000]×[1+(6000/3300)]×0.5943}+0.5943

[0076] Note: x by−1 because PAD2>CAD2

EANM2={[0.1667×2.8182]×0.5943}+0.5943

EANM2={0.4698×0.5943}+0.5943

EANM2=0.8735

LV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)]

LV1=−[0.2×250×(0.6−0.8735)/0.6]/[1.3^ (250/500)]

LV1=−[50×−0.4558]/1.1402

LV1=19.99

LV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)]

LV2=−[0.2×5000×(0.6−0.8735)/0.6]/[1.3^ (5000/3300)]

LV2=−[1000×−0.4558]/1.4882

LV2=306.276

Using the IDS™ with Multi-Agent (3 Agents) Therapy

[0077] When using a multi-agent regimen to treat patients it isnecessary to calculate the next best dose for each agent the patient isusing. The IDS™ technology in the form disclosed in applicant's U.S.Pat. No. 6,267,116 can only dose one agent at a time. The followingcalculations show how to use the concept of the IDS™ and the doseresponse methodology to perform multiple computations, each based on theproportional response which a particular agent has on the overallresponse that is to be achieved.

[0078] The concept underlying this multi-agent dosing model is that eachagent has some contribution to the overall effect. This contribution isdetermined by the amount of each agent the patient is using as well asthe intrinsic potency of each agent. The overall proportion of eachagent is determined by the amount of agent as it relates to the dosingrange. The overall proportion as well as the intrinsic potency of theagent is used to determine the total proportional effect which eachagent has on the surrogate marker. This parameter (FOE1, FOE2, or FOE3)is then inserted into the four-parameter equation (NAD) for calculatingdose by adjusting the proportional change in marker that is attributedto the activity of the agent.

[0079] To Calculate the First Agent

NAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1+LV1

[0080] To Calculate the Second Agent

NAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2

[0081] To Calculate the Third Agent

NAD3=CAD3{[<(DANM3−CANM3)×FOE3>/<1+(CAD3/HIGH3)>]×CAD3}

[0082] where:

EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1

EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1

EANM3={[(CAD3−PAD3)/PAD3]×[1+(PAD3/HIGH3)]×EANM2}+EANM2

[0083] if CANM1<DANM1 and EANM2>CANM1,

[0084] or

[0085] if CANM1>DANM1 and EANM2<CANM1,

[0086] then

LV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)]

[0087] if CANM1<DANM1 and EANM2<CANM1,

[0088] or

[0089] if CANM1>DANM1 and EANM2>CANM1,

[0090] then

LV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1][1.3^ (CAD/HIGH)]

[0091] if CANM2<DANM2 and EANM2>CANM2,

[0092] or

[0093] if CANM2>DANM2 and EANM2<CANM2,

[0094] then

LV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)]

[0095] if CANM2<DANM2 and EANM2>CANM2,

[0096] or

[0097] if CANM2>DANM2 and EANM2<CANM2,

[0098] then

LV2=[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)]

[0099] if CANM3<DANM3 and EANM3>CANM3,

[0100] or

[0101] if CANM3>DANM3 and EANM3>CANM3,

[0102] then

LV3=RESPONSE3×CAD3×(EANM3−CANM3)/CANM3[1.3^ (CAD3/HIGH3)]

[0103] if CANM3<DANM3 and EANM3<CANM3,

[0104] or

[0105] if CANM3>DANM3 and EANM3>CANM3,

[0106] then

LV3=−[RESPONSE3×CAD3×(CANM3−EANM3)/CANM3]/[1.3^ (CAD3/HIGH3)]

[0107] PAD1=Previous agent dose of the first agent

[0108] PAD2=Previous agent dose of the second agent

[0109] PAD3=Previous agent dose of the third agent

[0110] CAD1=Current agent dose of the first agent

[0111] CAD2=Current agent dose of the second agent

[0112] CAD3=Current agent dose of the third agent

[0113] NAD1=New agent dose of the first agent

[0114] NAD2=New agent dose of the second agent

[0115] NAD3=New agent dose of the third agent

[0116] PADM1=Previous agent numerical marker for the first agent

[0117] CANM1=Current agent numerical marker for the first agent

[0118] CANM2=Current agent numerical marker for the second agent

[0119] CANM3=Current agent numerical marker for the third agent

[0120] DANM1=Desired agent numerical marker for the first agent

[0121] DANM2=Desired agent numerical marker for the second agent

[0122] DANM3=Desired agent numerical marker for the third agent

[0123] FOE1=Factor of effect the first agent has on its associatednumerical marker

[0124] FOE2=Factor of effect the second agent has on its associatednumerical marker

[0125] FOE3=Factor of effect the third agent has on its associatednumerical marker

[0126] HIGH1=The input parameter that is the high dose range for thefirst agent

[0127] HIGH2=The input parameter that is the high dose range for thesecond agent

[0128] HIGH3=The input parameter that is the high dose range for thethird agent

[0129] RESPONSE1=Percent of total dose available for individualizingpatient dose of the first agent

[0130] RESPONSE2=Percent of total dose available for individualizingpatient dose of the second agent

[0131] RESPONSE3=Percent of total dose available for individualizingpatient dose of the third agent

[0132] 1.3^ (CAD1/HIGH1)=1.3 raised to an exponent of (CAD1/HIGH1)

[0133] 1.3^ (CAD2/HIGH2)=1.3 raised to an exponent of (CAD2/HIGH2)

[0134] 1.3^ (CAD3/HIGH3)=1.3 raised to an exponent of (CAD3/HIGH3)

[0135] To Calculate the Proportion of Effect Based on the Amount ofAgent and the Agent's Intrinsic Effect

[0136] Agent1 Effect=1

[0137] Agent2 Effect=1

[0138] Agent3 Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Agent3}\quad {Proportion}} = \frac{{Dose3}/{Range3}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent2}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect3}} = {\frac{{Dose3}/{Range3}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent3}\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}$${FOE2} = \frac{{Total}\quad {Proportional}\quad {Effect2}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}$${FOE3} = \frac{{Total}\quad {Proportional}\quad {Effect3}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}$

Using the IDS™ with Multi-Agent (n Agents) Therapy

[0139] The concept underlying this multi-agent dosing model is that eachagent has some contribution to the overall effect. This contribution isdetermined by the amount of each agent the patient is using as well asthe intrinsic potency of each agent. The overall proportion of eachagent is determined by the amount of agent as it relates to the dosingrange. The overall proportion as well as the intrinsic potency of theagent is used to determine the total proportional effect which eachagent has on the surrogate marker. This parameter (FOE1, FOE2 . . .FOEn) is then inserted into the four-parameter equation (NAD1, NAD2 . .. NADn) for calculating dose by adjusting the proportional change inmarker that is attributed to the activity of the agent.

[0140] To Calculate the First Agent

NAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1+LV1

[0141] To Calculate the Second Agent

NAD2=CAD2−{[<(DANM2−CANM2)×FOE1>/<1+(CAD2/HIGH2)>]×CAD2}+LV2

[0142] To Calculate the nth Agent

NADn=CADn−{[<(DANMn−CANMn)×FOEn>/<1+(CADn/HIGHn)>]×CADn}+LVn

[0143] where:

EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1

EANM2={[(CAD2PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1

EANMn={[(CADn−PADn)/PADn]×[1+(PADn/HIGHn)]×EANM_(n−1)}+EANM_(n−1)

[0144] if CANM1<DANM1 and EANM2>CANM1,

[0145] or

[0146] if CANM1>DANM1 and EANM2<CANM1,

[0147] then

LV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1[1.3^ (CAD1/HIGH1)]

[0148] if CANM1<DANM1 and EANM2<CANM1,

[0149] or

[0150] if CANM1>DANM1 and EANM2>CANM1,

[0151] then

LV1−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)]

[0152] if CANM2<DANM2 and EANM2>CANM2,

[0153] or

[0154] if CANM2>DANM2 and EANM2<CANM2,

[0155] then

LV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)]

[0156] if CANM2<DANM2 and EANM2<CANM2,

[0157] or

[0158] if CANM2>DANM2 and EANM2>CANM2,

[0159] then

LV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)]

[0160] . . .

LVn=−RESPONSEn×CADn×(EANMn×CANMn)/CANMn/[1.3^ (CADn/HIGHn)]

[0161] PAD1=Previous agent dose of the first agent

[0162] PAD2=Previous agent dose of the second agent

[0163] PADn=Previous agent dose of the nth agent

[0164] CAD1=Current agent dose of the first agent

[0165] CAD2=Current agent dose of the second agent

[0166] CADn=Current agent dose of the nth agent

[0167] NAD1=New agent dose of the first agent

[0168] NAD2=New agent dose of the second agent

[0169] NADn=New agent dose of the nth agent

[0170] PADM1=Previous agent numerical marker for the first agent

[0171] CANM1=Current agent numerical marker for the first agent

[0172] CANM2=Current agent numerical marker for the second agent

[0173] CANMn=Current agent numerical marker for the nth agent

[0174] DANM1=Desired agent numerical marker for the first agent

[0175] DANM2=Desired agent numerical marker for the second agent

[0176] DANMn=Desired agent numerical marker for the nth agent

[0177] FOE1=Factor of effect the first agent has on its associatednumerical marker

[0178] FOE2=Factor of effect the second agent has on its associatednumerical marker

[0179] FOEn=Factor of effect the nth agent has on its associatednumerical marker

[0180] HIGH1=The input parameter that is the high dose range for thefirst agent

[0181] HIGH2=The input parameter that is the high dose range for thesecond agent

[0182] HIGHn=The input parameter that is the high dose range for the nthagent

[0183] RESPONSE1=Percent of total dose available for individualizingpatient dose of the first agent

[0184] RESPONSE2=Percent of total dose available for individualizingpatient dose of the second agent

[0185] RESPONSEn=Percent of total dose available for individualizingpatient dose of the nth agent

[0186] 1.3^ (CAD1/HIGH1)=1.3 raised to an exponent of (CAD1/HIGH1)

[0187] 1.3^ (CAD2/HIGH2)=1.3 raised to an exponent of (CAD2/HIGH2)

[0188] 1.3^ (CADn/HIGHn)=1.3 raised to an exponent of (CADn/HIGHn)

[0189] To Calculate the Proportion of Effect Based on the Amount ofAgent and the Agent's Intrinsic Effect

[0190] Agent1 Effect=1

[0191] Agent2 Effect=1

[0192] Agent n Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Agent}\quad n\quad {Proportion}} = \frac{{Dose}\quad {n/{Range}}\quad n}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent2}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect}\quad n} = {\frac{{Dose}\quad {n/{Range}}\quad n}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent}\quad n\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}$${FOE2} = \frac{{Total}\quad {Proportional}\quad {Effect2}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}$${FOEn} = {\frac{{Total}\quad {Proportional}\quad {Effect}\quad n}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}.}$

[0193] Although the invention has been described in detail in theforegoing for the purpose of illustration, it is to be understood thatsuch detail is solely for that purpose and that variations can be madetherein by those of ordinary skill in the art without departing from thespirit and scope of the invention as defined by the following claims,including all equivalents thereof.

1. A method of calculating the next best dose for each agent of amulti-agent therapy which a patient may be using, comprising the stepsof: accepting as first inputs the patient's current doses of a pluralityof agents which the patient may be using; accepting as second inputs oneor more numerical markers indicating one or more responses of thepatient; and calculating new agent doses for said plurality of agents asa function of said first inputs, said second inputs, and contributionseach agent makes to an overall effect to be achieved by said multi-agenttherapy.
 2. The method according to claim 1, wherein said calculating isperformed as follows: To calculate the first agentNAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1}+LV1 ToCalculate the second AgengNAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2 where:EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1if CANM1<DANM1 and EANM2>CANM1, or if CANM1>DANM1 and EANM2<CANM1, thenLV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)] ifCANM1<DANM1 and EANM2<CANM1, or if CANM1>DANM1 and EANM2>CANM1, thenLV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)] ifCANM2<DANM2 and EANM2>CANM2, or if CANM2>DANM2 and EANM2<CANM2, thenLV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)] ifCANM2<DANM2 and EANM2<CANM2, or if CANM2>DANM2 and EANM2>CANM2, thenLV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)]PAD1=Previous agent dose of the first agent PAD2=Previous agent dose ofthe second agent CAD1=Current agent dose of the first agent CAD2=Currentagent dose of the second agent NAD1=New agent dose of the first agentNAD2=New agent dose of the second agent PADM1=Previous agent numericalmarker for the first agent CANM1=Current agent numerical marker for thefirst agent CANM2=Current agent numerical marker for the second agentDANM1=Desired agent numerical marker for the first agent DANM2=Desiredagent numerical marker for the second agent FOE1=Factor of effect thefirst agent has on its associated numerical marker FOE2=Factor of effectthe second agent has on its associated numerical marker HIGH1=The inputparameter that is the high dose range for the first agent HIGH2=Theinput parameter that is the high dose range for the second agentRESPONSE1=Percent of total dose available for individualizing patientdose of the first agent RESPONSE2=Percent of total dose available forindividualizing patient dose of the second agent 1.3^ (CAD1/HIGH1)=1.3raised to an exponent of (CAD1/HIGH1) 1.3^ (CAD2/HIGH2)=1.3 raised to anexponent of (CAD2/HIGH2) To Calculate the Proportion of Effect Based onthe Amount of Agent and the Agent's Intrinsic Effect Agent1 Effect=1Agent2 Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)} \times {Agent2}\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}}}$${FOE2} = {\frac{{Total}\quad {Proportional}\quad {Effect2}}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}}}.}$


3. The method according to claim 1, wherein said calculating isperformed as follows: To Calculate the First AgentNAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1}+LV1 ToCalculate the Second AgentNAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2 ToCalculate the Third AgentNAD3=CAD3−{[<(DANM3−CANM3)×FOE3>/<1+(CAD3/HIGH3)>]×CAD3}+LV3 where:EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1EANM3={[(CAD3−PAD3)/PAD3]×[1+(PAD3/HIGH3)]×EANM2}+EANM2if CANM1<DANM1 and EANM2>CANM1, or if CANM1>DANM1 and EANM2<CANM1, thenLV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)] ifCANM1<DANM1 and EANM2<CANM1, or if CANM1>DANM1 and EANM2>CANM1, thenLV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)] ifCANM2<DANM2 and EANM2>CANM2, or if CANM2>DANM2 and EANM2<CANM2, thenLV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)] ifCANM2<DANM2 and EANM2<CANM2, or if CANM2>DANM2 and EANM2>CANM2, thenLV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)] ifCANM3<DANM3 and EANM3>CANM3, or if CANM3>DANM3 and EANM3<CANM3, thenLV3=RESPONSE3×CAD3×(EANM3−CANM3)/CANM3/[1.3^ (CAD3/HIGH3)] ifCANM3<DANM3 and EANM3<CANM3, or if CANM3>DANM3 and EANM3>CANM3, thenLV3=−[RESPONSE3×CAD3×(CANM3−EANM3)/CANM3]/[1.3^ (CAD3/HIGH3)]PAD1=Previous agent dose of the first agent PAD2=Previous agent dose ofthe second agent PAD3=Previous agent dose of the third agentCAD1=Current agent dose of the first agent CAD2=Current agent dose ofthe second agent CAD3=Current agent dose of the third agent NAD1=Newagent dose of the first agent NAD2=New agent dose of the second agentNAD3=New agent dose of the third agent PADM1=Previous agent numericalmarker for the first agent CANM1=Current agent numerical marker for thefirst agent CANM2=Current agent numerical marker for the second agentCANM3=Current agent numerical marker for the third agent DANM1=Desiredagent numerical marker for the first agent DANM2=Desired agent numericalmarker for the second agent DANM3=Desired agent numerical marker for thethird agent FOE1=Factor of effect the first agent has on its associatednumerical marker FOE2=Factor of effect the second agent has on itsassociated numerical marker FOE3=Factor of effect the third agent has onits associated numerical marker HIGH1=The input parameter that is thehigh dose range for the first agent HIGH2=The input parameter that isthe high dose range for the second agent HIGH3=The input parameter thatis the high dose range for the third agent RESPONSE1=Percent of totaldose available for individualizing patient dose of the first agentRESPONSE2=Percent of total dose available for individualizing patientdose of the second agent RESPONSE3=Percent of total dose available forindividualizing patient dose of the third agent 1.3^ (CAD1/HIGH1)=1.3raised to an exponent of (CAD1/HIGH1) 1.3^ (CAD2/HIGH2)=1.3 raised to anexponent of (CAD2/HIGH2) 1.3^ (CAD3/HIGH3)=1.3 raised to an exponent of(CAD3/HIGH3) To Calculate the Proportion of Effect Based on the Amountof Agent and the Agent's Intrinsic Effect Agent1 Effect=1 Agent2Effect=1 Agent3 Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Agent3}\quad {Proportion}} = \frac{{Dose3}/{Range3}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent2}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect3}} = {\frac{{Dose3}/{Range3}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent3}\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}$${FOE2} = \frac{{Total}\quad {Proportional}\quad {Effect2}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}$${FOE3} = {\frac{{Total}\quad {Proportional}\quad {Effect3}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}.}$


4. The method according to claim 1, wherein said multi-agent therapyuses n agents, and said calculating is performed as follows: ToCalculate the First AgentNAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1+LV1 ToCalculate the Second AgentNAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2 ToCalculate the nth AgentNADn=CADn−{[<(DANMn−CANMn)×FOEn>/<1+(CADn/HIGHn)>]×CADn}+LVn where:EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1EANMn={[(CADn−PADn)/PADn]×[1+(PADn/HIGHn)]×EANM_(n−1)}+EANM_(n−1)if CANM1<DANM1 and EANM2>CANM1, or if CANM1>DANM1 and EANM2<CANM1, thenLV1−RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)] ifCANM1<DANM1 and EANM2<CANM1, or if CANM1>DANM1 and EANM2>CANM1, thenLV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)] ifCANM2<DANM2 and EANM2>CANM2, or if CANM2>DANM2 and EANM2<CANM2, thenLV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)] ifCANM2<DANM2 and EANM2<CANM2, or if CANM2>DANM2 and EANM2>CANM2, thenLV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)] . . .LVn=RESPONSEn×CADn×(EANM−CANMn)/CANMn/[1.3^ (CADn/HIGHn)] PAD1=Previousagent dose of the first agent PAD2=Previous agent dose of the secondagent PADn=Previous agent dose of the nth agent CAD1=Current agent doseof the first agent CAD2=Current agent dose of the second agentCADn=Current agent dose of the nth agent NAD1=New agent dose of thefirst agent NAD2=New agent dose of the second agent NADn=New agent doseof the nth agent PADM1=Previous agent numerical marker for the firstagent CANM1=Current agent numerical marker for the first agentCANM2=Current agent numerical marker for the second agent CANMn=Currentagent numerical marker for the nth agent DANM1=Desired agent numericalmarker for the first agent DANM2=Desired agent numerical marker for thesecond agent DANMn=Desired agent numerical marker for the nth agentFOE1=Factor of effect the first agent has on its associated numericalmarker FOE2=Factor of effect the second agent has on its associatednumerical marker FOEn=Factor of effect the nth agent has on itsassociated numerical marker HIGH1=The input parameter that is the highdose range for the first agent HIGH2=The input parameter that is thehigh dose range for the second agent HIGHn=The input parameter that isthe high dose range for the nth agent RESPONSE1=Percent of total doseavailable for individualizing patient dose of the first agentRESPONSE2=Percent of total dose available for individualizing patientdose of the second agent RESPONSEn=Percent of total dose available forindividualizing patient dose of the nth agent 1.3^ (CAD1/HIGH1)=1.3raised to an exponent of (CAD1/HIGH1) 1.3^ (CAD2/HIGH2)=1.3 raised to anexponent of (CAD2/HIGH2) 1.3^ (CADn/HIGHn)=1.3 raised to an exponent of(CADn/HIGHn) To Calculate the Proportion of Effect Based on the Amountof Agent and the Agent's Intrinsic Effect Agent1 Effect=1 Agent2Effect=1 Agentn Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Agent}\quad n\quad {Proportion}} = \frac{{Dose}\quad {n/{Range}}\quad n}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent2}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect}\quad n} = {\frac{{Dose}\quad {n/{Range}}\quad n}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent}\quad n\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}$${FOE2} = \frac{{Total}\quad {Proportional}\quad {Effect2}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}$${FOEn} = \frac{{Total}\quad {Proportional}\quad {Effect}\quad n}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}$


5. A storage device having stored thereon an ordered set of instructionswhich, when executed by a computer, performs a predetermined method,comprising: first means for accepting as first inputs a patient'scurrent doses of a plurality of agents which the patient may be using ina multi-agent therapy second means for accepting as second inputs one ormore numerical markers indicating one or more responses of the patient;and third means for calculating new agent doses for said plurality ofagents as a function of said first inputs, said second inputs, andcontributions which each agent makes to an overall effect to be achievedby said multi-agent therapy.
 6. The device according to claim 5, whereinsaid third means calculates said new agent doses as follows: ToCalculate the First AgentNAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1}+LV1 ToCalculate the Second AgentNAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2 where:EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1if CANM1<DANM1 and EANM2>CANM1, or if CANM1>DANM1 and EANM2<CANM1, thenLV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)] ifCANM1<DANM1 and EANM2<CANM1, or if CANM1>DANM1 and EANM2>CANM1, thenLV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)] ifCANM2<DANM2 and EANM2>CANM2, or if CANM2>DANM2 and EANM2<CANM2, thenLV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)] ifCANM2<DANM2 and EANM2<CANM2, or if CANM2>DANM2 and EANM2>CANM2, thenLV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)]PAD1=Previous agent dose of the first agent PAD2=Previous agent dose ofthe second agent CAD1=Current agent dose of the first agent CAD2=Currentagent dose of the second agent NAD1=New agent dose of the first agentNAD2=New agent dose of the second agent PADM1=Previous agent numericalmarker for the first agent CANM1=Current agent numerical marker for thefirst agent CANM2=Current agent numerical marker for the second agentDANM1=Desired agent numerical marker for the first agent DANM2=Desiredagent numerical marker for the second agent FOE1=Factor of effect thefirst agent has on its associated numerical marker FOE2=Factor of effectthe second agent has on its associated numerical marker HIGH1=The inputparameter that is the high dose range for the first agent HIGH2=Theinput parameter that is the high dose range for the second agentRESPONSE1=Percent of total dose available for individualizing patientdose of the first agent RESPONSE2=Percent of total dose available forindividualizing patient dose of the second agent 1.3^ (CAD1/HIGH1)=1.3raised to an exponent of (CAD1/HIGH1) 1.3^ (CAD2/HIGH2)=1.3 raised to anexponent of (CAD2/HIGH2) To Calculate the Proportion of Effect Based onthe Amount of Agent and the Agent's Intrinsic Effect Agent1 Effect=1Agent2 Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)} \times {Agent2}\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}}}$${FOE2} = {\frac{{Total}\quad {Proportional}\quad {Effect2}}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}}}.}$


7. The device according to claim 5, wherein said third means calculatessaid new agent doses as follows: To Calculate the First AgentNAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM>/<1+(CAD1/HIGH1)>]×CAD1}+LV1 ToCalculate the Second AgentNAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2 ToCalculate the Third AgentNAD3=CAD3−{[<(DANM3−CANM3)×FOE3>/<1+(CAD3/HIGH3)>]×CAD3}+LV3 where:EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1EANM3={[(CAD3−PAD3)/PAD3]×[1+(PAD3/HIGH3)]×EANM2}+EANM2if CANM1<DANM1 and EANM2>CANM1, or if CANM1>DANM1 and EANM2<CANM1, thenLV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)] ifCANM1<DANM1 and EANM2<CANM1, or if CANM1>DANM1 and EANM2>CANM1, thenLV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)] ifCANM2<DANM2 and EANM2>CANM2, or if CANM2>DANM2 and EANM2<CANM2, thenLV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)] ifCANM2<DANM2 and EANM2<CANM2, or if CANM2>DANM2 and EANM2>CANM2, thenLV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)] ifCANM3<DANM3 and EANM3>CANM3, or if CANM3>DANM3 and EANM3<CANM3, thenLV3=RESPONSE3×CAD3×(EANM3−CANM3)/CANM3/[1.3^ (CAD3/HIGH3)] ifCANM3<DANM3 and EANM3<CANM3, or if CANM3>DANM3 and EANM3>CANM3, thenLV3=−[RESPONSE3×CAD3×(CANM3−EANM3)/CANM3]/[1.3^ (CAD3/HIGH3)]PAD1=Previous agent dose of the first agent PAD2=Previous agent dose ofthe second agent PAD3=Previous agent dose of the third agentCAD1=Current agent dose of the first agent CAD2=Current agent dose ofthe second agent CAD3=Current agent dose of the third agent NAD1=Newagent dose of the first agent NAD2=New agent dose of the second agentNAD3=New agent dose of the third agent PADM1=Previous agent numericalmarker for the first agent CANM1=Current agent numerical marker for thefirst agent CANM2=Current agent numerical marker for the second agentCANM3=Current agent numerical marker for the third agent DANM1=Desiredagent numerical marker for the first agent DANM2=Desired agent numericalmarker for the second agent DANM3=Desired agent numerical marker for thethird agent FOE1=Factor of effect the first agent has on its associatednumerical marker FOE2=Factor of effect the second agent has on itsassociated numerical marker FOE3=Factor of effect the third agent has onits associated numerical marker HIGH1=The input parameter that is thehigh dose range for the first agent HIGH2=The input parameter that isthe high dose range for the second agent HIGH3=The input parameter thatis the high dose range for the third agent RESPONSE1=Percent of totaldose available for individualizing patient dose of the first agentRESPONSE2=Percent of total dose available for individualizing patientdose of the second agent RESPONSE3=Percent of total dose available forindividualizing patient dose of the third agent 1.3^ (CAD1/HIGH1)=1.3raised to an exponent of (CAD1/HIGH1) 1.3^ (CAD2/HIGH2)=1.3 raised to anexponent of (CAD2/HIGH2) 1.3^ (CAD3/HIGH3)=1.3 raised to an exponent of(CAD3/HIGH3) To Calculate the Proportion of Effect Based on the Amountof Agent and the Agent's Intrinsic Effect Agent1 Effect=1 Agent2Effect=1 Agent3 Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Agent3}\quad {Proportion}} = \frac{{Dose3}/{Range3}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent2}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect3}} = {\frac{{Dose3}/{Range3}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent3}\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}$${FOE2} = \frac{{Total}\quad {Proportional}\quad {Effect2}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}$${FOE3} = {\frac{{Total}\quad {Proportional}\quad {Effect3}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}.}$


8. The device according to claim 5, wherein said multi-agent therapyuses n agents, and said third means calculates said new agent does asfollows: To Calculate the First AgentNAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1+LV1 ToCalculate the Second AgentNAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2 ToCalculate the nth AgentNADn=CADn−{[<(DANMn−CANMn)×FOEn>/<1+(CADn/HIGHn)>]×CADn}+LVn where:EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1EANMn={[(CADn−PADn)/PADn]×[1+(PADn/HIGHn)]×EANM_(n−1)}+EANM_(n−1)if CANM1<DANM1 and EANM2>CANM1, or if CANM1>DANM1 and EANM2<CANM1, thenLV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)] ifCANM1<DANM1 and EANM2<CANM1, or if CANM1>DANM1 and EANM2>CANM1, thenLV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)] ifCANM2<DANM2 and EANM2>CANM2, or if CANM2>DANM2 and EANM2<CANM2, thenLV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)] ifCANM2<DANM2 and EANM2<CANM2, or if CANM2>DANM2 and EANM2>CANM2, thenLV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2) . . .LVn=RESPONSEn×CADn×(EANM−CANMn)/CANMn/[1.3^ (CADn/HIGHn)] PAD1=Previousagent dose of the first agent PAD2=Previous agent dose of the secondagent PADn=Previous agent dose of the nth agent CAD1=Current agent doseof the first agent CAD2=Current agent dose of the second agentCADn=Current agent dose of the nth agent NAD1=New agent dose of thefirst agent NAD2=New agent dose of the second agent NADn=New agent doseof the nth agent PADM1=Previous agent numerical marker for the firstagent CANM1=Current agent numerical marker for the first agentCANM2=Current agent numerical marker for the second agent CANMn=Currentagent numerical marker for the nth agent DANM1=Desired agent numericalmarker for the first agent DANM2=Desired agent numerical marker for thesecond agent DANMn=Desired agent numerical marker for the nth agentFOE1=Factor of effect the first agent has on its associated numericalmarker FOE2=Factor of effect the second agent has on its associatednumerical marker FOEn=Factor of effect the nth agent has on itsassociated numerical marker HIGH1=The input parameter that is the highdose range for the first agent HIGH2=The input parameter that is thehigh dose range for the second agent HIGHn=The input parameter that isthe high dose range for the nth agent RESPONSE1=Percent of total doseavailable for individualizing patient dose of the first agentRESPONSE2=Percent of total dose available for individualizing patientdose of the second agent RESPONSEn=Percent of total dose available forindividualizing patient dose of the nth agent 1.3^ (CAD1/HIGH1)=1.3raised to an exponent of (CAD1/HIGH1) 1.3^ (CAD2/HIGH2)=1.3 raised to anexponent of (CAD2/HIGH2) 1.3^ (CADn/HIGHn)=1.3 raised to an exponent of(CADn/HIGHn) To Calculate the Proportion of Effect Based on the Amountof Agent and the Agent's Intrinsic Effect Agent1 Effect=1 Agent2Effect=1 Agent n Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Agent}\quad n\quad {Proportion}} = \frac{{Dose}\quad {n/{Range}}\quad n}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent2}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect}\quad n} = {\frac{{Dose}\quad {n/{Range}}\quad n}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent}\quad n\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}$${FOE2} = \frac{{Total}\quad {Proportional}\quad {Effect2}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}$${FOEn} = {\frac{{Total}\quad {Proportional}\quad {Effect}\quad n}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}.}$


9. An apparatus for calculating the next best dose for each agent of amulti-agent therapy which a patient may be using, comprising: firstmeans for accepting as first inputs the patient's current doses of aplurality of agents which the patient may be using; second means foraccepting as second inputs one or more numerical markers indicating oneor more responses of the patient; and third means for calculating newagent doses for said plurality of agents as a function of said firstinputs, said second inputs, and contributions which each agent makes toan overall effect to be achieved by said multi-agent therapy.
 10. Theapparatus according to claim 9, wherein said third means calculates saidnew agent doses as follows: To Calculate the First AgentNAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1}+LV1 ToCalculate the Second AgentNAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2 where:EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1if CANM1<DANM1 and EANM2>CANM1, or if CANM1>DANM1 and EANM2<CANM1, thenLV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)] ifCANM1<DANM1 and EANM2<CANM1, or if CANM1>DANM1 and EANM2>CANM1, thenLV1−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)] ifCANM2<DANM2 and EANM2>CANM2, or if CANM2>DANM2 and EANM2<CANM2, thenLV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)] ifCANM2<DANM2 and EANM2<CANM2, or if CANM2>DANM2 and EANM2>CANM2, thenLV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)]PAD1=Previous agent dose of the first agent PAD2=Previous agent dose ofthe second agent CAD1=Current agent dose of the first agent CAD2=Currentagent dose of the second agent NAD1=New agent dose of the first agentNAD2=New agent dose of the second agent PADM1=Previous agent numericalmarker for the first agent CANM1=Current agent numerical marker for thefirst agent CANM2=Current agent numerical marker for the second agentDANM1=Desired agent numerical marker for the first agent DANM2=Desiredagent numerical marker for the second agent FOE1=Factor of effect thefirst agent has on its associated numerical marker FOE2=Factor of effectthe second agent has on its associated numerical marker HIGH1=The inputparameter that is the high dose range for the first agent HIGH2=Theinput parameter that is the high dose range for the second agentRESPONSE1=Percent of total dose available for individualizing patientdose of the first agent RESPONSE2=Percent of total dose available forindividualizing patient dose of the second agent 1.3^ (CAD1/HIGH1)=1.3raised to an exponent of (CAD1/HIGH1) 1.3^ (CAD2/HIGH2)=1.3 raised to anexponent of (CAD2/HIGH2) To Calculate the Proportion of Effect Based onthe Amount of Agent and the Agent's Intrinsic Effect Agent1 Effect=1Agent2 Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}}} \right)} \times {Agent2}\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}}}$${FOE2} = {\frac{{Total}\quad {Proportional}\quad {Effect2}}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}}}.}$


11. The apparatus according to claim 9, wherein said third meanscalculates said new agent doses as follows: To Calculate the First AgentNAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1}+LV1 ToCalculate the Second AgentNAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2 ToCalculate the Third AgentNAD3=CAD3−{[<(DANM3−CANM3)×FOE3>/<1+(CAD3/HIGH3)>]×CAD3}+LV3 where:EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1EANM3={[(CAD3−PAD3)/PAD3]×[1+(PAD3/HIGH3)]×EANM2}+EANM1if CANM1<DANM1 and EANM2>CANM1, or if CANM1>DANM1 and EANM2<CANM1, thenLV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)] ifCANM1<DANM1 and EANM2<CANM1, or if CANM1>DANM1 and EANM2>CANM1, thenLV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)] ifCANM2<DANM2 and EANM2>CANM2, or if CANM2>DANM2 and EANM2<CANM2, thenLV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)] ifCANM2<DANM2 and EANM2<CANM2, or if CANM2>DANM2 and EANM2>CANM2, thenLV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^ (CAD2/HIGH2)] ifCANM3<DANM3 and EANM3>CANM3, or if CANM3>DANM3 and EANM3<CANM3, thenLV3=RESPONSE3×CAD3×(EANM3−CANM3)/CANM3/[1.3^ (CAD3/HIGH3)] ifCANM3<DANM3 and EANM3<CANM3, or if CANM3>DANM3 and EANM3>CANM3, thenLV3=−[RESPONSE3×CAD3×(CANM3−EANM3)/CANM3]/[1.3^ (CAD3/HIGH3)]PAD1=Previous agent dose of the first agent PAD2=Previous agent dose ofthe second agent PAD3=Previous agent dose of the third agentCAD1=Current agent dose of the first agent CAD2=Current agent dose ofthe second agent CAD3=Current agent dose of the third agent NAD1=Newagent dose of the first agent NAD2=New agent dose of the second agentNAD3=New agent dose of the third agent PADM1=Previous agent numericalmarker for the first agent CANM1=Current agent numerical marker for thefirst agent CANM2=Current agent numerical marker for the second agentCANM3=Current agent numerical marker for the third agent DANM1=Desiredagent numerical marker for the first agent DANM2=Desired agent numericalmarker for the second agent DANM3=Desired agent numerical marker for thethird agent FOE1=Factor of effect the first agent has on its associatednumerical marker FOE2=Factor of effect the second agent has on itsassociated numerical marker FOE3=Factor of effect the third agent has onits associated numerical marker HIGH1=The input parameter that is thehigh dose range for the first agent HIGH2=The input parameter that isthe high dose range for the second agent HIGH3=The input parameter thatis the high dose range for the third agent RESPONSE1=Percent of totaldose available for individualizing patient dose of the first agentRESPONSE2=Percent of total dose available for individualizing patientdose of the second agent RESPONSE3=Percent of total dose available forindividualizing patient dose of the third agent 1.3^ (CAD1/HIGH1)=1.3raised to an exponent of(CAD1/HIGH1) 1.3^ (CAD2/HIGH2)=1.3 raised to anexponent of (CAD2/HIGH2) 1.3^ (CAD3/HIGH3)=1.3 raised to an exponent of(CAD3/HIGH3) To Calculate the Proportion of Effect Based on the Amountof Agent and the Agent's Intrinsic Effect Agent1 Effect=1 Agent2Effect=1 Agent3 Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Agent3}\quad {Proportion}} = \frac{{Dose3}/{Range3}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent2}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect3}} = {\frac{{Dose3}/{Range3}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {{Dose3}/{Range3}}} \right)} \times {Agent3}\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}$${FOE2} = \frac{{Total}\quad {Proportional}\quad {Effect2}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}$${FOE3} = {\frac{{Total}\quad {Proportional}\quad {Effect3}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} +} \\{{Total}\quad {Proportional}\quad {Effect3}}\end{matrix}}.}$


12. The apparatus according to claim 9, wherein said multi-agent therapyuses n agents, and said third means calculates said new agent doses asfollows: To Calculate the First AgentNAD1=CAD1−{[<(DANM1−CANM1)×FOE1/CANM1>/<1+(CAD1/HIGH1)>]×CAD1+LV1 ToCalculate the Second AgentNAD2=CAD2−{[<(DANM2−CANM2)×FOE2>/<1+(CAD2/HIGH2)>]×CAD2}+LV2 ToCalculate the nth AgentNADn=CADn−{[<(DANMn−CANMn)×FOEn>/<1+(CADn/HIGHn)>]×CADn}+LVn where:EANM1={[(CAD1−PAD1)/PAD1]×[1+(PAD1/HIGH1)]×PADM1}+PADM1EANM2={[(CAD2−PAD2)/PAD2]×[1+(PAD2/HIGH2)]×EANM1}+EANM1EANMn={[(CADn−PADn)/PADn]×[1+(PADn/HIGHn)]×EANM_(n−1)}+EANM_(n−1)if CANM1<DANM1 and EANM2>CANM1, or if CANM1>DANM1 and EANM2<CANM1, thenLV1=RESPONSE1×CAD1×(EANM2−CANM1)/CANM1/[1.3^ (CAD1/HIGH1)] ifCANM1<DANM1 and EANM2<CANM1, or if CANM1>DANM1 and EANM2>CANM1, thenLV1=−[RESPONSE1×CAD1×(CANM1−EANM2)/CANM1]/[1.3^ (CAD/HIGH)] ifCANM2<DANM2 and EANM2>CANM2, or if CANM2>DANM2 and EANM2<CANM2, thenLV2=RESPONSE2×CAD2×(EANM2−CANM2)/CANM2/[1.3^ (CAD2/HIGH2)] ifCANM2<DANM2 and EANM2<CANM2, or if CANM2>DANM2 and EANM2>CANM2, thenLV2=−[RESPONSE2×CAD2×(CANM2−EANM2)/CANM2]/[1.3^(CAD2/HIGH2)]LVn=RESPONSEn×CADn×(EANM−CANMn)/CANMn/[1.3^ (CADn/HIGHn)]PAD1=Previous agent dose of the first agent PAD2=Previous agent dose ofthe second agent PADn=Previous agent dose of the nth agent CAD1=Currentagent dose of the first agent CAD2=Current agent dose of the secondagent CADn=Current agent dose of the nth agent NAD1=New agent dose ofthe first agent NAD2=New agent dose of the second agent NADn=New agentdose of the nth agent PADM1=Previous agent numerical marker for thefirst agent CANM1=Current agent numerical marker for the first agentCANM2=Current agent numerical marker for the second agent CANMn=Currentagent numerical marker for the nth agent DANM1=Desired agent numericalmarker for the first agent DANM2=Desired agent numerical marker for thesecond agent DANMn=Desired agent numerical marker for the nth agentFOE1=Factor of effect the first agent has on its associated numericalmarker FOE2=Factor of effect the second agent has on its associatednumerical marker FOEn=Factor of effect the nth agent has on itsassociated numerical marker HIGH1=The input parameter that is the highdose range for the first agent HIGH2=The input parameter that is thehigh dose range for the second agent HIGHn=The input parameter that isthe high dose range for the nth agent RESPONSE1=Percent of total doseavailable for individualizing patient dose of the first agentRESPONSE2=Percent of total dose available for individualizing patientdose of the second agent RESPONSEn=Percent of total dose available forindividualizing patient dose of the nth agent 1.3^ (CAD1/HIGH1)=1.3raised to an exponent of (CAD1/HIGH1) 1.3^ (CAD2/HIGH2)=1.3 raised to anexponent of (CAD2/HIGH2) 1.3^ (CADn/HIGHn)=1.3 raised to an exponent of(CADn/HIGHn) To Calculate the Proportion of Effect Based on the Amountof Agent and the Agent's Intrinsic Effect Agent1 Effect=1 Agent2Effect=1 Agent n Effect=1${{Agent1}\quad {Proportion}} = \frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Agent2}\quad {Proportion}} = \frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Agent}\quad n\quad {Proportion}} = \frac{{Dose}\quad {n/{Range}}\quad n}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)}$${{Total}\quad {Proportional}\quad {Effect1}} = {\frac{{Dose1}/{Range1}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent1}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect2}} = {\frac{{Dose2}/{Range2}}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent2}\quad {Effect}}$${{Total}\quad {Proportional}\quad {Effect}\quad n} = {\frac{{Dose}\quad {n/{Range}}\quad n}{\left( {{{Dose1}/{Range1}} + {{Dose2}/{Range2}} + {\ldots \quad {Dose}\quad {n/{Range}}\quad n}} \right)} \times {Agent}\quad n\quad {Effect}}$${FOE1} = \frac{{Total}\quad {Proportional}\quad {Effect1}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}$${FOE2} = \frac{{Total}\quad {Proportional}\quad {Effect2}}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}$${FOEn} = {\frac{{Total}\quad {Proportional}\quad {Effect}\quad n}{\begin{matrix}{{{Total}\quad {Proportional}\quad {Effect1}} + {{Total}\quad {Proportional}\quad {Effect2}} + \ldots} \\{{Total}\quad {Proportional}\quad {Effect}\quad n}\end{matrix}}.}$